Adeno-associated viruses (AAV) make ideal gene delivery vector candidates because they are non-pathogenic, lowly immunogenic and broadly tropic. Despite their great promise in gene therapy clinical trials for severe diseases including hemophilia and muscular dystrophy, there is a lack of understanding of fundamental aspects of the AAV life cycle. AAV tissue tropism is known to be dependent on certain rate-limiting steps within the virus life cycle, including cellular entry and trafficking from the plasma membrane to the nucleus. Further elucidation is necessary to dissect the mechanisms that direct these steps, and specifically identify the host factors that facilitate these processes. To discover novel host factors that are involved in virus entry and trafficking, we recently performed an unbiased, human genetic screen. We identified several proteins as critically important for AAV infection, including a poorly characterized transmembrane protein that we have since named AAV Receptor (AAVR). We found AAVR to be essential for the transduction of a wide array of AAV serotypes in vitro and in vivo. We observed that AAVR could bind directly to AAV particles, and that overexpression of AAVR in vitro led to enhanced AAV susceptibility. Of particular interest was the capacity of AAVR to recycle through a remarkably similar endocytic path as AAV particles. This suggests a potential post-entry role for AAVR in particle trafficking. Building upon these findings, our long-term goal seeks to elucidate the molecular mechanisms that govern rate-limiting processes within AAV?s life cycle in order to understand more about the biology of AAV, as well as harness this knowledge to improve AAV?s versatility as a vector. We intend to do this by determining: (i) what the relationship is between receptor engagement and intracellular viral trafficking, (ii) how AAVR contributes to viral tropism in vivo, and (iii) how the other major hits identified in our screen function in mediating AAV trafficking.